Carcinogenesis Advance Access originally published online on January 16, 2007
Carcinogenesis 2007 28(6):1178-1187; doi:10.1093/carcin/bgl255
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WNT5A—target of CUTL1 and potent modulator of tumor cell migration and invasion in pancreatic cancer
Department of Internal Medicine I, University of Ulm, 89081 Ulm, Germany
1 Department of Pathology, University Hospital Schleswig-Holstein, Campus Kiel, 24105 Kiel, Germany
2 Cancer Research UK London Research Institute, London WC2A 3PX, UK
3 Division of Gastroenterology and Endocrinology, Department of Internal Medicine, Philipps-University, Baldinger Strasse, 35043 Marburg, Germany
* To whom correspondence should be addressed. Tel: +49 6421 286 1714; Fax: +49 6421 286 8922; Email: michlp{at}med.uni-marburg.de
Previously, we have identified the transcription factor CUTL1 as an important mediator of tumor invasion and target of tumor growth factor-beta. Using high-throughput approaches, we identified several putative downstream effectors of CUTL1, among them WNT5A, a secreted member of the Wnt multigene family. The aim of this study was to investigate the role of WNT5A as a novel target of CUTL1 in pancreatic cancer. CUTL1 and WNT5A were stably over-expressed as well as transiently and stably knocked down by RNA interference. Effects on proliferation, migration and invasiveness were investigated by thymidine incorporation, Boyden chamber experiments and time-lapse microscopy. Expression of WNT5A in pancreatic cancer tissues was analyzed by real-time polymerase chain reaction (RT–PCR) and immunohistochemistry. We found that CUTL1 transcriptionally up-regulated WNT5A on RNA, protein and promoter level. WNT5A significantly enhanced migration, proliferation and invasiveness, mediating the pro-invasive effects of CUTL1 to a major extent. WNT5A effects were accompanied by a marked modulation of marker genes associated with epithelial–mesenchymal transition. Using RT–PCR and immunohistochemistry, we found that WNT5A is up-regulated early during pancreatic cancerogenesis in pancreatic intraepithelial neoplasias lesions and in invasive pancreatic adenocarcinomas, as compared with normal pancreas tissues. These data identify WNT5A as important target of CUTL1 and as novel mediator of invasiveness and tumor progression in pancreatic cancer.
Abbreviations: CaMKII, calmodulin-dependent protein kinase II; EMT, epithelial–mesenchymal transition; GSK, glycogen synthose kinase-3beta; LiCl, lithium chloride; PanIN, pancreatic intraepithelial neoplasias; PKC, protein kinase C; RT–PCR, real-time polymerase chain reaction; siRNA, small interfering RNA; TGF-beta, tumor growth factor-beta
These authors contribute equally to this work. Received July 20, 2006; revised December 7, 2006; accepted December 19, 2006.
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